Key Points
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The serine–threonine liver kinase B1 (LKB1) is inactivated in Peutz–Jeghers syndrome and a large percentage of sporadic non-small cell lung carcinomas and cervical carcinomas.
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LKB1 acts a master upstream kinase, directly phosphorylating and activating AMP-activated protein kinase (AMPK) and a family of 12 related kinases that have crucial roles in cell growth, metabolism and polarity.
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The LKB1–AMPK pathway serves as a metabolic checkpoint in the cell, arresting cell growth in conditions of low intracellular ATP levels, such as in low nutrient conditions.
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One of the central mitogenic pathways that is suppressed by LKB1 and AMPK signalling is the mTOR complex 1 pathway, which is inhibited through AMPK phosphorylation of tuberous sclerosis complex 2 and regulatory associated protein of mTOR (raptor).
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Overnutrition and hyperglycaemia can suppress LKB1–AMPK signalling, which might contribute to an increased cancer risk in patients who are obese or diabetic. Conversely, activation of LKB1–AMPK signalling might contribute to the suppression of cancer risk that is associated with exercise and caloric restriction. Will AMPK-activating drugs, including existing diabetes therapeutics, find clinical usefulness as anticancer agents?
Abstract
In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine–threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
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Acknowledgements
We regret being unable to cite the work of many of our colleagues owing to space limitations. The authors thank K. Lamia for critical reading and editing of the manuscript. The authors' research is funded by grants from the National Institutes of Health (R01 DK080425 and P01 CA120964), American Cancer Society and V Foundation for Cancer Research to R.J.S. D.B.S. was supported by training grant T32 CA009370 to the Salk Institute Center for Cancer Research. R.J.S. is an early career scientist of the Howard Hughes Medical Institute.
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DATABASES
National Cancer Institute Drug Dictionary
[18F] 2-fluoro-2-deoxy-D-glucose
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Glossary
- Peutz–Jeghers syndrome
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A disorder that is characterized by the development of gastrointestinal hamartomas and an increased predisposition to many other malignancies, including those arising in colon, breast, ovarian, pancreatic and lung tissues.
- Tuberous sclerosis complex
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A familial tumour syndrome that is induced through mutation of the mTOR complex 1 regulators TSC1 and TSC2.
- Steatosis
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Excess intracellular lipid accumulation, which can occur, for example, in the liver of patients who are diabetic or obese.
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Shackelford, D., Shaw, R. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9, 563–575 (2009). https://doi.org/10.1038/nrc2676
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DOI: https://doi.org/10.1038/nrc2676
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